6-halogen-3-hydroxy-benzoates and process of preparing them



6-HALOGEN-3-HYDROXY-BENZOATES 'AND PROCESS or PREPARING THEM Heinrich Ruschig, Bad Soden (Taunus), and Gerhard Korger and Georg Lammler, Frankfurt am Main, Germany, assignors to Farbwerke .Hoechst Aktiengesellschaft vormals Meister Lucius & Bruning, Frankfurt am Main, Germany, a corporation of Germany No Drawing. Application December 20,1955 Serial No. 554,136

Claims priority, application Germany December 27, 1954 6 Claims. (Cl. 260-473) The present invention relates to compounds which are suitable as anthelminthics and which correspond to the general formula Y Hal COH

II OH wherein Hal represents chlorine, bromine or iodine and R an alkyl radical with 4 to 5 carbon atoms, and to the process for the manufacture of such compounds.

A great number of compounds belonging to entirely difierent classes have already been employed for the chemotherapy of helminthiases in human beings and animals. Apart from different drugs such as ascaridol and santonin there have-also been recommended, chlorinated hydrocarbons such as tetrachloroethylene, substituted phenols and their derivatives, such as para-chlorocarvacrol, para-bromothymol, hexylresorcinol, paratertiary-amyl-phenol propionate. Other compounds, for instance dystuifs, such as crystal violet and different heterocyclic compounds, such as phenothiazine, do. not come into consideration owing to their different constitution. In practice, however, it has been found that'the known compounds partly only possess specific action on certain kinds of intestinal worms and that the therapeutic range of all these compounds is relatively small so that, even when the therapeutic dose'is only little exceeded,

disagreeable symptoms result.

Now we have found that 6-halogen-3-hydroxy-benzo-.

ates are obtained, which, apart from a satisfactory action on the parasites, possess at the same time a high therapeutic index and a broad therapeutic range, by'esterifying 6-halogen-3-hydroxy-benzoic acids according to known methods with alcohols containing a linear or branched aliphatic chainwith .4.to 5 carbon atoms. These 6-halogen-3-hydroxy-benzoates can also be prepared by reesterification. V

As esterification components there may, for instance, be used n-butanol, isobutanol and isoamyl alcohol.

As halogen substituents in the benzene nucleus there are suited chlorine, bromine and iodine.

The reaction of the process of the present invention can, for instance, be carried out according to the following methods:

(a) By direct esterification in the presence of catalytically effective substances, for instance, in the presence of gaseous hydrogen halides, concentrated sulphuric acid or concentrated phosphoric acid.

(b) By reesterification which can'be carried out in the usual manner, for instance, in the presence of an alcoholate as catalyst.

Naturally, there may also be employed other methods known for the preparation of esters.

According to the invention, the reaction may also be carried out in the presence or absence of a diluent. As such may advantageously be used an excess of the alcohol required for the esterification. The reaction may be carried out at room temperature as well as at elevated temperatures, the reaction at elevated temperatures being terminated in lesser time. i

The compounds obtained according to the process of the present invention are valuable medicaments and are particularly suited as anthelminthics. Apart from a very' good tolerability they possess a marked eflicacy.

It is remarkable that, in spite of the presence of a free phenolic .hydroxy group, the therapeutic range of the compounds obtained according to the process of the present'invention is'considerablyfsuperior to that of the anthelminthics used at present. This is surprising since the small therapeutic range of various known anthel minthics on the basis of phenolsis attributed to the presence of free phenolic hydroxy groups. We have'found that the good tolerability is only shown by the benzoates which have the following special constitution- Hal O OH Whilst' the therapeutic indexhereinafter defined amounts to 5.0-6.5 for -ascaridol, to 5.0-6.0 for hexyl resorcinol, and to 5.0-6.0 for para-bromothymol, a.considerably higher index isfound for the compounds of the present invention. 6-chloro-3-hydroXy-n-butyl-benzoate, for instance, has a therapeutic index of 12-14;

The therapeuticfindex is the quotient from the minimum toxic dose per kg. determined per es in the-mouse and from the curative dose per kg. determined in the dog. The data result from tests on the ankylostomiasis and ascaridiasis of the dog. The known 2.4-dichloro-isoarnyl benzoate did not show any effect on the dog suffering from ascaridiasis-when applied in a dose nearly "twice as large as the curative dose of the 6-chloro- 3 -hydroxy-nbutyl-benzoate.

The pharmacological data of some compounds obtained 7 according to the process of the: present invention and their therapeutic indices', which aresuperiorto those of the -known 6 chlor'o '3-hydroxy-ethyl benzoate (No. 5),

are tobe seen from the following'tablez" Min. toxic Thera- N 0. Compound Cur. dose per dose per peutic kg. of dog kg. of index mouse 1 6-Chloro-3-hydroxy-iso- 0.3 cc 7.0 00-.-- 23 amyl benzoate. 2.-. 6- Chloro-3-hydroxy-n- 0.4-0.5 gm..- 5.0 gm... 10-12 butyl benzoate. 3 6-Oh1oro-3-hydroxy-lso- 0.4 cc 7.0 00.... 17

butyl benzoate. 4.....-- 6-Bromo-3-hydroxy-n- 0.3-0.4 00.... 5.0 00--.- 12-14 butyl benzoate. 5....... 6-Chloro-3-hydroxy ethyl 0.5-0.6 gm-.. 3.6 gm... 6-7 benzoate.

Patented Apr. 8,1958 A The following examples serve to illustrate the inveninto the boiling solution of 344 grams of 6-chloro-3-h'ydroXy-benzoic acid in '800 grams of n-butanol and the whole is then boiled for about 12 hours. The butanol in excess is distilled off ascompletely as possible under reduced pressure, the residue is taken up in ether and the ethereal solution is shakentwice with a sodium bicarbonate solution. The ether isdistilled off and the remaining residue is fractionated under reduced pressure. The 6-chloro-3-hydroxy-n-butyl benzoate passes over in an analytically pure form at 203-204 C. under a pressure of 11-12 mm. of mercury as a yellowish oil which soon solidifies in the. receiving vessel. 390 1 grams (85 percent of the theoretical yield). The white crystals obtained upon recrystallisation from cyclohexane melt at 4243 C.

EXAMPLE 2 6-chlor0-3-hydroxy'isoamyl-benzoate Gaseous hydrogen chloride. is introduced within 7 hours into the solution of 86 grams of 6-chloro-3-hydroxybenzoic acid in 250 grams of isoamyl alcohol heated to about 100 C. The whole is then heated for another 7 hours at 100 C. and is worked up as described in Example 1. The 6-chloro-3-hydroxy isoamyl-benzoate is obtained in the form of a non-crystalline, weakly yellowish oil boiling at 173176 C. under a pressure of 1-2 mm. of mercury. The yield amounts to 100 grams (82 percent of the theoretical yield).

EXAMPLE 3 6-chloro-3-hydroxy-isobutyl-benzoate A mixture of 120 grams of 6-chloro-3-hydroxy-benzoic i acid, 160 grams of isobutanol and 30 grams of concentrated sulfuric acid is boiled for hours under reflux. Thereupon ether is added and the mixture is shaken several times and successively with water, with a sodium" EXAMPLE 4 6-broma-3-hydroxy-n-butyl-benzoate Gaseous hydrogen chloride is introduced within 6 hours into. the boiling solution of 100 grams of 6-bromo-3hydroxy-benzoic acid in 240 grams of n-butanol and the whole is then boiled for another 6 hours. The ,butanol in excess is evaporated as completely as possible under reduced pressure, theresidueis taken up in ether and the.

ethereal solution is shaken repeatedly. with a sodium bicarbonate solution. The ether is distilled off and-the The yield amounts to' residue that remains is fractionated three times under reduced pressure. The 6 bromo 3 hydroxy-n-butylbenzoate distils over as a yellowish oil at 172-176 C. under a pressureof 0.9-1.2 mm. of mercury. The yield amounts to 78 grams (62 percent of the theoretical yield). We claim: 1. 6-halogen-3-hydroxy-benzoates of the general for mula Hal

wherein Hal is a member selected from the group consisting of chlorine; and bromine and R represents an alkyl radical containing 4 to 5 carbon atoms.

2. The compound of the formula The compound of the formula 4. The compound of the formula l CH:

Q-m-o-cm-og il 0H5 0H 5. The compound of the formula 6. The process of preparing 6-halogen-3-hydroxybenzoates of the general formula IIal 

1. 6-HALOGEN-3-HYDROXY-BENZOATES OF THE GENERAL FORMULA 